The occurrence of resistances against all commercial anthelmintics seems to be a growing problem in the area of veterinary medicine. The extensive utilisation of anthelmintics to manage the control of nematodes resulted in significant selection of highly resistant worm populations. Therefore, the spread of resistance against all anthelmintic drug classes threatens effective worm control in cattle, goats, sheep and horses. Furthermore, successful prevention of heartworm disease in dogs, which currently solely relies on the utilisation of macrocyclic lactones, is in danger due to the unequivocal proof of macrocyclic lactone resistance in heartworm in some regions of the United States of America and Brazil.
Although resistance of human helminths against anthelmintics seems currently to be rare, the spread of anthelmintic resistance in the veterinary field as mentioned before needs to be considered in the treatment of human helminthosis as well. Persistent underdosed treatments against filariosis may lead to highly resistant genotypes and resistances have already been described for certain anthelminthics (e.g. praziquantel, benzimidazole and niclosamide).
Therefore, resistance-breaking anthelmintics with new molecular modes of action are urgently required.
It is an object of the present invention to provide compounds which can be used as anthelmintics in the medical, especially veterinary, field with a satisfactory or improved anthelmintic activity against a broad spectrum of helminths, particularly at relatively low dosages, for the control, treatment and/or prevention of infections with helminths in animals and humans, preferably without any adverse toxic effects to the treated organism.
Certain pyrazolopyrimidine carboxamides are related to their activity increasing the efficacy of the endogenous ligand 3-hydroxybutyrates as described in Journal of Medicinal Chemistry, 55, (7), 3563-3567. Other pyrazolopyrimidine carboxamides are described as allosteric agonists for the high affinity nicotinic acid receptor GPR109A as in Bioorganic & Medicinal Chemistry Letters, 18, (18), 4948-4951. Furthermore, pyrazolopyrimidine carboxamides are known as protein kinase modulators (EP1918291), as active ingredients for treatment or prevention of skin dieseases (WO 2009041663) or as NAD(P)H oxidase inhibitors (WO 2003091256). A certain method for a library synthesis process of said compounds is described in Journal of Combinatorial Chemistry, 9, (3), 507-512.
However, the state of the art does not describe the new pyrazolopyrimidine derivatives of general formula (I) of the present invention as described and defined herein.
It has now been found, and this constitutes the basis of the present invention, that the compounds of the present invention have surprising and advantageous properties.
In particular, the compounds of the present invention have surprisingly been found to effectively interact with Slo-1 of nematodes. This interaction is characterized by achieving paralysis/inhibition in particular of gastro-intestinal nematodes, of free-living nematodes, and of filariae, for which data are given in the biological experimental section. Therefore the compounds of the present invention may be used as anthelmintics for the control, treatment and/or prevention of gastro-intestinal and extra-intestinal helminth infections, in particular gastro-intestinal and extra-intestinal infections with nematodes, including filariae.